Intestinal homeostasis: identification of the factors that influence the balance between regulatory and effector cells in the intestine and how alterations in these can lead to chronic intestinal inflammation. (360G-Wellcome-044651_Z_95_E)

Using mouse models we have shown that colitis can develop as a consequence of excessive innate or T cell dependent responses and that these can be controlled by immune suppressive regulatory T cells (TR). Our recent studies suggest compartmentalization of the pathological response with IL-23 driving local intestinal inflammation and IL-12 mediating the systemic response. We will further characterize the cellular and molecular pathways of IL-23 driven intestinal inflammation, including IL-17 production, to identify their role in innate and T cell dependent colitis. Foxp3 and IL-10 indicator mice will be used to analyse the distribution of bacteria-induced and naturally arising TR cells in vivo as they respond to inflammation and determine their functional properties in distinct anatomical compartments. CD103+ mucosal DC's plays a key role in TR function and will determine how this DC subset influences the balance between effector and TR responses. We have also newly identified the G-protein coupled receptor Gpr 83 as a potential marker for TR cells and using Gpr83-/- mice we will assess its functional role. The results of these studies will facilitate the development of novel therapeutics for chronic inflammatory diseases via the manipulation of TR cells and tissue specific inflammatory pathways.